Category Archives: Blognosis

The rich tradition of Jewish involvement in the medical profession is the subject of an exhibit now showing at New York’s Yeshiva University Museum. Trail of the Magic Bullet: The Jewish Encounter with Modern Medicine, 1860-1960 explores the social, cultural, religious, and scientific aspects of that relationship during the era of modern medicine.

Dr. Paul Ehrlich / Photo taken by Miriam E. Tucker with permission from Yeshiva University Museum

The exhibit’s title references Dr. Paul Ehrlich’s “magic bullet” salvarsan, the syphilis cure he discovered that was used until penicillin became available in the 1940s. One of five Jewish physicians profiled, Dr. Ehrlich (1854-1915) won the Nobel Prize in 1908 for his “Side Chain” theory, which helped explain how antibodies neutralize invaders. Born in Germany, Dr. Ehrlich never renounced his Judaism despite experiences with anti-Semitism.

Jews were often unwelcome in established areas of medicine such as surgery, so they embraced newly-emerging specialties including psychiatry, neurology and dermatology, according to the exhibit. In Germany, dermatology was called Judenhaut, or “Jews’ skin,” and psychoanalysis was known as the “Jewish Science.” A wall of the exhibit honors 28 Jewish pioneers in these fields, including psychoanalysis founder Dr. Sigmund Freud (1856-1939).

Another section illustrates the Jewish community’s role in establishing hospitals such as Newark (NJ) Beth Israel Hospital in 1924, as well as public health-oriented social service organizations and visiting nurse programs in the United States and abroad. While these institutions were founded to aid underserved segments of the Jewish population, they evolved to serve entire communities of Jews and non-Jews.

Discrimination and quotas, widespread nationwide until the 1950s, are addressed toward the end. One of several abhorrent displayed quotes is attributed to 1920-1935 Yale Medical School Dean Dr. Milton Charles Winternitz, addressing his admission committee: “Never admit more than five Jews, take only two Italian Catholics, and take no blacks at all.” Albert Einstein College of Medicine was founded by Yeshiva University as the first American medical school established under Jewish auspices, specifically with the aim of helping prospective Jewish medical students bypass such restrictions.

Magic Bullet ends with a modern examination of medical ethics from a Jewish perspective. A 15-minute film entitled Heal, You Shall Heal features physicians, rabbis, ethicists, and patients offering perspectives on genetic testing/pregnancy termination in the case of abnormality and end-of-life decisions. Rabbi Daniel S. Nevins, a dean at the Jewish Theological Seminary, says this: “As much as modern medical technology has given us a sense that we understand what is going on with the birth and death process, the truth is that these are moments of great mystery. It’s important for us to be humble in such moments.”

Trail of the Magic Bullet: The Jewish Encounter with Modern Medicine, 1860-1960 runs through Aug. 12, 2012.

The current U.S. influenza seasonal epidemic, the mildest in years, is in its death throes, based on infection trends over the past several weeks, including the most recent data released on May 11 by the Centers for Disease Control and Prevention.

During the week that ended on May 5, 13.7% of U.S. respiratory surveillance specimens tested positive for influenza, continuing the clear downhill slope of U.S, flu cases since this season’s U.S. epidemic peaked at 30% positive during the week of March 11-17. The CDC hasn’t yet declared the current, 2011-2012 flu-season’s epidemic, which started in late February, officially over—it can’t until the influenza-positive rate falls back below 10%–but the epidemic curve’s steep downward track (see graphic) is as well defined as the far side of L’Alpe d’Huez.

graphic courtesy of the CDC

With the current influenza epidemic nearly ended, the season’s numbers paint a decidedly benign picture. So far, 22 children have died from influenza; if that figure continues to grow as it has so far it will top out as the lowest since the CDC began collecting these data in 2004.

Other markers of how mild the 2011-2012 season has been include the number of U.S. patients hospitalized for influenza, which sits below past seasons, and the proportion of deaths attributable to pneumonia or influenza has hovered below the epidemic threshold for that measure all season.

During a winter and spring where the influenza world focused on mammalian-transmissible H5N1 flu, strains dubbed by some the “doomsday” virus, having such a mild seasonal flu season tossed at us can’t help but be seen as some ironic, natural-world prank. On a purely rationale basis, year-to-year variations in seasonal flu have nothing whatsoever to do with the looming danger from H5N1 flu, but with this infectious-disease juxtaposition I can’t help but imagine that somewhere, off in the distance, I hear a quiet, cosmic chortle.

Just when it seemed like consensus existed on how to handle the hot potato of mammalian-transmissible H5N1 influenza, the public release on Friday afternoon of a letter sent April 12 from the respected influenza and public health researcher Dr. Michael Osterholm to a National Institutes of Health official collapsed the apparent consensus like a house of cards.

To recap: On March 29 and 30, the U.S. government’s National Science Advisory Board for Biosafety (NSABB), organized by the NIH’s Office of Science Policy, met to reconsider the NSABB’s original decision last December that said the paper written by Dr. Yoshihiro Kawaoka and another paper by Dr. Ron Fouchier on their respective efforts to produce and study H5N1 mutants transmissible by air from ferret to ferret should only be published without the methods sections, a way to prevent release of the details on how they developed these potentially dangerous mutant strains. The initial NSABB recommendation to allow publication of only the redacted papers failed to win support from a panel convened by the World Health Organization in February, creating a conflict between the NSABB (and hence the NIH) and the WHO. Claiming that new data first revealed to the WHO group led to the different outcome, Dr. Anthony S. Fauci, director of the National Institute of Allergy and Infectious Diseases — the U.S. agency that sponsored the work of both Dr. Kawaoka and Dr. Fouchier — called on the NSABB to rethink its initial decision, which resulted in the NSABB reversing itself on March 30 and supporting full publication, in a unanimous vote for Dr. Kawaoka’s work, and in a 12-6 vote for Dr. Fouchier’s. So, by early April, the NSABB (and hence, pending official U.S. policy) and the WHO agreed that full H5N1 publication could proceed. Peace reigned across the land.

Dr. Michael Osterholm

Until 2 weeks later, when Dr. Osterholm an NSABB member, upset the tranquility by writing his bombshell letter to Dr. Amy Patterson, NIH’s associate director for Science Policy. In it, Dr. Osterholm took vigorous swipes at how the NIH set up the NSABB’s reconsideration session and detailed his grave concerns about public release of how the H5N1 work was done. Both “Science” and “Nature” received the letter on April 13, and according to a report in “Nature,” Dr. Osterholm said he was not the source for the leak.

“I believe the agenda and speakers for the March 29 and 30 NSABB meeting as determined by the Office of Biotechnology Activities [part of the NIH’s Office of Science Policy] staff and other U.S. government officials was designed to produce the outcome that occurred,” Dr. Osterholm charged in his letter. “It represented a very ‘one-sided’ picture of the risk-benefit of the dissemination of the information in these manuscripts. The agenda was not designed to promote a balanced reconsideration of the manuscripts.”

A major problem, he said, was that the “experts that addressed [the March NSABB session] have a real conflict of interest in that their laboratories are involved in this same type of work and the results of our deliberations directly affect them too.” The same problem occurred at the WHO meeting in February, he added.

Dr. Osterholm tempered his charge by saying he did not “suggest that there was a sinister motive by the U.S. government,” but still leveled a hefty blast, saying “I believe there was a bias toward finding a solution that was a lot less about robust science- and policy-based risk-benefit and more about how to get us out of this difficult situation.”

The upshot was that in the revised decision NSABB, U.S. policy makers, and researchers failed to “come to grips with the very difficult task of managing dual-use research of concern and the dissemination of potentially harmful information to those who might intentionally or unintentionally use that information in a harmful way.” His worry is — if not in this case — “will the Board ever find a bright line for redacting publication” of any future research that could potentially threaten public health?

Dr. Osterholm cited a major danger if details of this research became fully public: “A ferret-to-ferret experiment is expensive and technically demanding, and could only be done by a handful of labs in the world. Once the mutations are public, individuals … in many other labs could generate the mutants in a few weeks given several thousand dollars for gene synthesis,” using reverse genetics.

Finally, Dr. Osterholm questioned the public-health benefit from full release of the methods sections of the two H5N1 papers. “The most important aspect of the results in these two studies on surveillance and control has already been accomplished namely alerting the world to the possibility that H5N1 influenza virus surely can become a mammalian-transmitted virus and poses real pandemic potential.” Publication of more details from the research will not add to that alert, nor would it immediately help in the development or production of countermeasures against a potential H5N1 pandemic, he said.

Despite his concerns over full disclosure of the methods, Dr. Osterholm affirmed his overall support for this H5N1 research in a comment to “Nature” on Friday. “I have been and continue to be a supporter of this kind of research,” he told the journal.

When researchers reported earlier this week at the American College of Cardiology’s annual meeting results from the TRA 2P-TIMI 50 trial, which tested a novel anticoagulant drug, vorapaxar, for preventing cardiovascular death, myocardial infarction (MI), and stroke in stable patients with cardiovascular disease, the results showed a questionable balance between benefit and bleeding risk that only looked good if you squinted and confined the analysis to patients with just a history of MI, no history of stroke, a body weight of at least 60 kg, and, ideally, those who were younger than 75 years old. Even within this pared-down universe, experts differed on whether vorapaxar had an unequivocal net benefit after taking into account the bleeding risk it caused.

But if vorapaxar someday gets FDA approval and appears on the U.S. market, physicians will face the tricky calculus of how to use it compared with the other new, potent antithrombotic drugs.

blood clot/courtesy Janice Carr; Public Health Image Library

Looking at vorapaxar’s performance in patients with stable cardiovascular disease, it was hard not to recall last November’s report on the ATLAS ACS 2-TIMI 51 trial, which tested adding a 2.5 mg b.i.d. dosage of another new anticoagulant drug, rivaroxaban, in acute coronary syndrome (ACS) patients also treated with aspirin and clopidogrel. In ATLAS, adding this small dose of rivaroxaban led to benefit and a bleeding risk that was strikingly similar to the pattern seen with vorapaxar in TRA 2P. Rivaroxaban on top of aspirin and clopidogrel produced an absolute, 1.6% cut in the combined rate of cardiovascular death, MI, or stroke while boosting the rate of major bleeds by an absolute 1.2%, and the rate of intracranial bleeds by 0.2%. The new vorapaxar results showed that in the best-case subgroup, adding the drug to aspirin and clopidogrel cut cardiovascular death, MI, or stroke by an absolute 1.9%, while boosting major bleeds by 1.0% and intracranial hemorrhage by 0.2%.

A big difference in the two analyses was that the benefits and risk seen with 2.5 mg rivaroxaban was in the entire study population of 5,100 patients, with no need to resort to subgroup analyses. The vorapaxar result was in about 9,500 patients, roughly 70% of all patients enrolled in the trial. Another big difference was the major impact of rivaroxaban was on cutting cardiovascular deaths. Vorapaxar’s main effect was to lower nonfatal MIs. It cut cardiovascular deaths too, but not as well as low-dose rivaroxaban.

Many experts whom I spoke with at the meeting seemed confident that low-dose rivaroxaban is on track for FDA approval later this year for treating ACS patients. Whether Merck, the company developing vorapaxar, will seek FDA approval for its drug in stable patients based on the TRA 2P data remains to be seen.

But while rivaroxaban won’t receive labeling for treating non-ACS patients, all that separates an ACS patient and a patient who is stable but with a history of prior MI is time; in fact, just a few weeks or months. The point at which an acute ACS patient becomes a stable, post-MI patient is pretty murky. Would anyone consider treating a stable, post-ACS patient with low-dose rivaroxaban? The labeling probably won’t cover it, but will the temptation be there? And the what-ifs don’t stop there.

Both the low-dose rivaroxaban study and the vorapaxar study used aspirin and clopidogrel as standard, background treatment. But U.S. physicians are increasingly switching from clopidogrel to the newer, more potent antiplatelet drugs already on the market, prasugrel and ticagrelor, several experts told me at ACC. Putting a patient on prasugrel or ticagrelor plus aspirin will likely preclude any thought of also adding rivaroxaban, not to mention vorapaxar. These combinations have not been tested, and given the bleeding risks that these drugs pose individually, the idea of using them in combination is downright scary.

After several years when clopidogrel plus aspirin reigned alone as the top treatment for preventing atherothrombotic events, the last few years brought a flurry of new agents. How these drugs compare and relate to each other, and how they are optimally used alone or in combination, will take several more years to sort out.

What a difference a few years, and a new generation, has meant for the fortunes of drug-eluting coronary stents.

In the late summer of 2006, at that year’s meeting of the European Society of Cardiology, the specter of stent thrombosis first rose around the drug eluting coronary stents of that era, the sirolimus- and paclitaxel-eluting devices. The concern led to an abrupt plunge in the use of drug-eluting stents, routine use of more prolonged dual antiplatelet therapy with aspirin and clopidogrel, and eventually the development and marketing of second-generation stents, which used new drugs—everolimus and zotarolimus—and new polymers to bind the drugs to the stent.

Over the past couple of years, the second generation has given drug-eluting stents a renewed, more robust profile. And now, a new meta-analysis published online in The Lancet brings the best news so far for the new generation: the cobalt-chromium everloimus-eluting stent–marketed as both Xience V and Promus—fared significantly better than bare metal stents in their rates of stent thrombosis both 1 and 2 years after placement, and the cobalt-chromium everolimus-eluting stent also significantly surpassed all of its competition, both first- and other second-generation coronary stents.

image courtesy Abbott Vascular

The Lancet article that described the meta-analysis, which included 49 trials with more than 50,000 patients, called the finding “a paradigm shift,” something that, if confirmed in a prospective trial, “would have profound clinical implications.” A drug-eluting coronary stent that’s actually substantially safer than a bare-metal stent for the important safety endpoint of stent thrombosis. Who would have thought it possible just a few years ago?

The editorial accompanying the new analysis, by New Zealand cardiologists John Ormiston and Mark Webster, cautions that as a meta-analysis the finding can strictly be regarded as only hypothesis generating, but they also note that a head-to-head randomized comparison of the cobalt-chromium everolimus-eluting stent and a bare-metal stent for this endpoint is unlikely to ever happen. They also said that while the new finding was “unexpected,” the cobalt-chromium everolimus-eluting stent must now be “regarded as the standard against which future design improvements [in stent technology] are compared.” The “firestorm” about stent safety, first set ablaze 5.5 years ago at the ESC “is now barely smoldering,” they concluded.

The authors of the meta-analysis said that the suggestion that this everolimus-eluting stent could actually best bare-metal stents for stent thrombosis first became plausible at last August’s ESC, in results from the EXAMINATION study, which compared the two stent types in about 1,500 acute myocardial infarction patients. The meta-analysis pooled results from two head-to-head comparisons of the cobalt-chromium everolimus-eluting stent against a bare-metal stent in a total of about 3,800 patients (including the EXAMINATION population), and found that the everolimus-eluting device cut the 1-year thrombosis rate by 86% and the 2-year rate by 65% compared with bare-metal stents. The cobalt-chromium everolimus-eluting model also significantly surpassed every other first- and second-generation drug-eluting stent for their 1-year rate of definite stent thrombosis.

Hypothesis generating or not, it’s a result that cardiologists will find hard to ignore.

It sounds a bit audacious for the results of a study with 113 randomized patients to change the face of U.S. management of acute, ischemic stroke patients, but Dr. Saver laid out a compelling scenario at the meeting. In essence, it’s the right result for the right device at the right time.

Acute stroke care in America is already poised at an important threshold. Last week, The Joint Commission, the U.S. organization responsible for accrediting health-care institutions, announced their newly crafted criteria for credentialing Comprehensive Stroke Centers. By next year, Dr. Saver predicted, 100-200 such centers will have received this designation into the highest tier of acute stroke management. He expects all these locations to treat patients with the Solitaire stent, as well as a few others. “At least 250” U.S. sites should be using it within the next couple of years, he told me. In addition, an emergency-medicine culture already exists to ambulance acute stroke patients to one of the 1,000 Primary Stroke Centers that now exist in America, use imaging to identify the ones who qualify for intravenous lytic therapy with tissue plasminogen activator (t-PA), start administering the drug, and then transfer them to a center that can apply more advanced care, a strategy know as “drip and ship.”

Having the Solitaire device takes this approach a step further, making it “drip, ship, and grip,” he told me, with grip being the step when the thrombus causing the stroke is engaged and removed.

“We stand poised at a new era, our first experience with highly effective cerebral revascularization,” he said at the meeting last week. “The open secret in our field is that t-PA or the devices now available deliver treatment that fails most of the time.” Intravenous t-PA by itself produces full recanalization in about 5% of patients, while existing devices up this to 25%; for Solitaire the rate was 61% in the new randomized study, and the rate of full or partial recanalization was 83%.

This new level of success with Solitaire will make a big difference in how widely the treatment gets used, he told me.

Dr. Jeffrey Saver MITCHEL ZOLER/Zoler/Elsevier Global Medical News

“I think motivations [to use endovascular interventions] will shift with a more reliable device. That will drive wider uptake.” He called it a “paradigm shift” and a “game changer.”

Rapid application of effective endovascular therapy “was the vision of acute stroke care that was a hazy dream when I first became a stroke neurologist 20 years ago,” Dr. Saver said. “I think that in the next few months and years it will become the reality.”

The U.S. National Science Advisory Board for Biosecurity weighed in publicly for the first time yesterday about research on mammalian-adapted H5N1 influenza, and the Board’s verdict was that the research is important and needs to go forward, but must be done very carefully, with oversight, and without releasing potentially dangerous details to the general public.

Perhaps most importantly, aside from the NSABB giving a general thumbs up to current and future H5N1 research, the Board cried out a clear warning for the world to prepare for a naturally generated H5N1 threat. As acting NSABB chairman Paul S. Keim said in a Q&A that accompanied the Board’s statement in Nature, “It is important to convey how unprepared, on every level, the world is for a H5N1 pandemic.” A highly pathogenic form of H5N1 flu, which the recent work by Kawaoka and Fouchier made clear is a potential natural development, would produce an “unimaginable catastrophe” worldwide, the NSABB said in its statement yesterday.

dual use research/courtesy Library of Congress

The Board also coined a new phrase to categorize the H5N1 work: “dual use research.” Dual in that the research “could be used for good or bad purposes.” That, of course, is why the Board wants the methods part of the work kept off the public record. “Publishing these experiments in detail would provide information to some person, organization, or government that would help them to develop similar mammal-adapted influenza A/H5N1 viruses for harmful purposes,” the NSABB said. The Board said the threat from this work is so high that the life sciences have now “reached a crossroads,” similar to what physics faced in the 1940s with the development of nuclear weapons.

But despite the threat from widespread release of the research methods—a risk that the NSABB says it believes can be blunted by simply not publishing the information—the Board firmly endorsed the work done so far and its continuation. That contrasts with the continued call from some critics to shut it down completely.

H5N1 research is “a well-intended effort to discover evolutionary routes by which influenza A/H5N1 viruses might adapt to humans. Such knowledge may be valuable for improving the public-health response to a looming natural threat,” the NSABB said. “We acknowledge that there are clear benefits to be realized for the public good in alerting humanity of this potential threat and in pursuing those aspects of this work that will allow greater preparedness and the potential development of novel strategies leading to future disease control.”